2015 Recap: PTSD and RA, a Smoking Gun?

Psychological treatment could reduce arthritis burden

Our Year in Review series highlights some of the major medical news stories of 2015. In rheumatology, we reported that women with severe post-traumatic stress disorder have a markedly elevated risk of developing rheumatoid arthritis. Here is the original article, published Aug. 13. In a companion story, we report on what has happened since.

The presence of four or more symptoms of PTSD was associated with a 76% increased risk of incident rheumatoid arthritis compared with no history or symptoms of trauma (HR 1.76, 95% CI 1.16 to 2.67), according to Yvonne C. Lee, MD, of Harvard Medical School in Boston, and colleagues.

There also was a dose-response relationship. Compared with women who reported no trauma and no symptoms of PTSD, those who had trauma exposure but no symptoms of PTSD had a 25% increased risk (HR 1.25), and those having one to three PTSD symptoms had a 31% increased risk (HR 1.31, P for trend 0.01), the researchers reported online in Arthritis Care & Research.

A Link With Inflammation

In some individuals, exposure to a highly traumatic event can result in intrusive memories and re-experiencing the event, avoidance, and heightened arousal problems such as insomnia, irritability, and loss of concentration -- PTSD.

"The mechanism of this association may be through dysregulation of the hypothalamic-pituitary-adrenal-axis response, leading to heightened systemic inflammation," Lee and colleagues wrote.

"I noticed years ago in working with [military] veterans that people who have severe chronic PTSD also had inflammatory diseases," said Joseph A. Boscarino, PhD, of the Geisinger Clinic in Danville, Penn. "They tended to have diseases like rheumatoid arthritis and psoriasis and it was thought to relate to an increase in the immune response."

In another study of twin pairs from the Vietnam Era Twin Registry, Boscarino and colleagues found that those in the highest quartile of PTSD symptoms were 3.8 times more likely to have rheumatoid arthritis than those in the lowest quartile.

And in a further longitudinal study of 1,500 veterans who had rheumatoid arthritis, 11.7% had been diagnosed with PTSD.

"Those with PTSD had faster disease progression, more severe rheumatoid arthritis, and were more affected by the disease progression," Boscarino said.

"Compared to patients without a psychiatric diagnosis, a diagnosis of PTSD was associated with a pain score that was a mean of ~1 unit higher when using a 1-10 scale over follow-up (beta=0.96, P<0.0001)," he and his colleagues wrote.

They also noted that that difference in self-reported pain was "similar in magnitude to improvements in pain attributed to the receipt of biologic anti-tumor necrosis factor therapy."

While these studies suggested an association between PTSD and rheumatoid arthritis, they were limited in that the study populations consisted primarily of male military veterans and did not address the differential risk according to seropositivity for rheumatoid factor or anti-cyclic citrullinated peptide. Some research has suggested that risk factors for seropositive and seronegative rheumatoid arthritis differ.

Nor did the previous research attempt to assess the influence of smoking on the association, which is important because smoking itself increases the risk of rheumatoid arthritis and "has the potential to be both a confounder and a mediator of the association between PTSD and chronic illness," Lee and colleagues noted.

Therefore, to further explore these concerns, Lee and colleagues analyzed data from the Nurses' Health Study II, which began enrolling participants in 1989 and includes more than 116,000 women who regularly respond to questionnaires about health and lifestyle, including smoking.

A history of exposure to traumatic events such as motor vehicle accidents, physical assault, and natural disasters was elicited by the Brief Trauma Questionnaire, which was administered to participants in 2008. Factors included were age at the time of exposure and number and duration of symptoms.

The current analysis included 49,693 women without rheumatoid arthritis or lupus at baseline and who responded to the trauma questionnaire.

Of these, 14,445 reported having no trauma and no PTSD, 25,486 had trauma but no PTSD, 4,874 had one to three symptoms of PTSD, and 4,888 had four or more symptoms.

Mean age was 35 and the majority were white. Current smoking was reported by 8% of women with four or more symptoms compared with 5.6% of those with fewer than four symptoms (P<0.0001). Women with more than four symptoms also more commonly reported more than 10 pack-years of smoking (22.1% versus 16.1%, P<0.0001).

Between 1989 and 2011, there were 239 incident cases of rheumatoid arthritis.

The increased overall risk for rheumatoid arthritis among women with multiple PTSD symptoms was also seen among those who developed seropositive (HR 1.68, 95% CI 1.01 to 2.79) and seronegative (HR 1.97, 95% CI 0.93 to 4.17) disease, although the risk in seronegative patients was not statistically significant.

A dose-response relationship also was seen for the seropositive group (trauma but no symptoms, HR 1.16, one to three PTSD symptoms, HR 1.13, P for trend 0.05).

The Smoking Gun?

The researchers then addressed the issue of smoking as a potential confounder or mediator in the analysis, explaining that "a confounder is associated with both the predictor (PTSD) and the outcome (rheumatoid arthritis) but is not on the causal pathway between the predictor and the outcome." That concern can be assessed by including smoking as a variable in the multivariate analysis, they noted.

In contrast, "a mediator is associated with both the predictor and the outcome and is also on the causal pathway." To account for this, the researchers conducted a subgroup analysis that excluded women who had begun smoking before the onset of PTSD.

In the multivariate analysis, the researchers determined beforehand that only a change of more than 10% in the hazard ratio for rheumatoid arthritis could be considered a "meaningful influence of smoking" on the association of PTSD.

They found that the hazard ratio after adjustment for smoking was 1.60 (95% CI 1.05 to 2.43), which did not reach the 10% cutoff, indicating that smoking was not a confounder.

In addition, in the subgroup analysis of women with four or more symptoms who began to smoke after PTSD onset, the risk remained similar (HR 1.68, 95% CI 1.04 to 2.70, meaning that smoking also was not a mediator and the risk for rheumatoid arthritis was therefore independent of smoking, and that other factors must be involved.

Further complicating the relationship with smoking is a recently identified genetic association, according to Boscarino.

"Something interesting we discovered recently is that the CHRNA5 gene that predicts smoking also affects anxiety, fear, and stress," he said.

He and his colleagues reported that the CHRNA5 gene, along with three other genetic loci "involving biologic pathways encompassing inflammatory mechanisms, nicotine dependence, substance misuse, sleep regulation, and fear circuitry, among others, are associated with PTSD and interact with levels of trauma exposure."

"It appears that people with PTSD have multiple risk factors. It's not only inflammation, but they also have genes that are associated with smoking and anxiety and also are associated with increased inflammation -- there's an overlap," he said.

Further studies assessing these associations will need to be large and prospective, to consider a possible cause and effect relationship, he noted.

"And the theory is that if you could treat them psychologically, you should be able to reduce the burden of RA disease," Boscarino said.

Limitations of Lee's study included the possibility of selection bias and the fact that causality cannot be assumed in the analysis.

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